PROJECT SUMMARY Opioid overdose deaths and the rise in problematic opioid use patterns that indicate the development of opioid use disorder (OUD) have reached crisis levels in the United States. Behavioral interventions coupled with medication-assisted treatment (MAT), such as the partial opioid agonist buprenorphine, reduce repeated opioid overdoses and substantially improve the odds of successful recovery in OUD. While current MAT is a chief adjunct in the proper management of OUD patients, this crisis has crystalized the need to identify novel, non- opioid therapeutics for this chronic medical disorder. Neuroplasticity within the interconnected nodes of the meso-corticostriatal circuit contributes to the enhanced motivational attributes of abused drugs and drug- associated cues, key factors in sustained OUD and relapse. In this light, we identified ghrelin as an endogenous regulator of this therapeutically-relevant circuit. Ghrelin acts by binding to the growth hormone secretagogue receptor 1? (GHS1?R) to transduce several physiological and behavioral processes, including the reward- related effects of opioid agonists. We discovered that systemic administration of a GHS1?R antagonist/inverse agonist dose-dependently attenuated self-administration of the abused opioid analgesic oxycodone as well as oxycodone-seeking. During the UG3 phase, we will leverage this new knowledge and employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1?R antagonist/inverse agonist developed by Pfizer which has advanced into clinical trials. We will assess PF5190457 to block oxycodone intake without abuse liability and to suppress oxycodone withdrawal and relapse-like behaviors in male and female rats. We will also determine the drug metabolism and pharmacokinetics (DMPK) interaction between oxycodone and PF5190457 and brain penetrability of PF5190457 in opioid-experienced rats. With achievement of the UG3 preclinical milestones, we will work with NIDA to partner with Pfizer for Phase 1 clinical studies in non-treatment seeking OUD participants through assessment of the safety and tolerability of PF5190457 following oral oxycodone administration relative to placebo, the DMPK profile of oral oxycodone in OUD participants following PF5190457 (vs. placebo) dosing, and the subjective response to oral oxycodone following PF5190457 (vs. placebo). The second goal of the UH3 phase is to develop the preclinical data to support the prospect that PF5190457 may serve as an adjuvant therapy to reduce the dose of buprenorphine required for MAT. The small molecule GHS1?R antagonist/inverse agonist PF5190457 is a novel target for an OUD medication and achievement of the UG3 milestones demonstrating its effectiveness in the comprehensive preclinical analyses will provide the foundation for the UH3 to characterize PF5190457 as a potential treatment for OUD. The outcomes of the UG3/UH3 will have a sustained, powerful impact in our field with the prospect to validate a novel medication for OUD.